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AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below
J Russell Huie1, Ellen D Stuck1, Kuan H Lee2
1Department of Neurological Surgery, Brain and Spinal Injury Center, University of California San Francisco , San Francisco, California 94110.
Eneuro
|December 16, 2015
Summary
Painful peripheral injuries after spinal cord injury (SCI) impair motor recovery by altering synaptic plasticity in motor neurons. This study reveals a mechanism involving AMPA receptors (AMPARs) and identifies a potential therapeutic target for improving outcomes.
Area of Science:
- Neuroscience
- Spinal Cord Injury Research
- Synaptic Plasticity
Background:
- Spinal cord injury (SCI) frequently occurs with peripheral injuries, which negatively impact motor recovery.
- Painful peripheral stimuli are known to cause maladaptive synaptic plasticity in the spinal cord dorsal horn.
- The mechanisms by which peripheral injuries affect motor neuron plasticity below the SCI level remain largely unknown.
Purpose of the Study:
- To investigate whether peripheral nociceptive stimuli induce experience-dependent maladaptive plasticity in ventral horn motor neurons in rats with a complete SCI.
- To identify the specific molecular changes in AMPA receptors (AMPARs) within motor neurons following peripheral injury.
- To explore the potential of targeting these AMPAR changes for therapeutic intervention.
Main Methods:
- Quantitative biochemistry was used to analyze AMPAR subunit phosphorylation and localization in the injured spinal cord.
- Automated confocal microscopy tracked changes in synaptic GluA1 and GluA2 in lumbar ventral horn motor neurons over time.
- Optical fractionation assessed the removal of GluA2 from neuronal plasma membranes.
- A selective calcium-permeable AMPAR (CP-AMPAR) antagonist was administered to evaluate its effect on plasticity and motor function.
Main Results:
- Intermittent nociceptive stimulation (INS) rapidly increased phosphorylated GluA1 and decreased GluA2 at synapses in the injured spinal cord.
- A time-dependent increase in synaptic GluA1 and decrease in synaptic GluA2 was observed in motor neurons after INS.
- GluA2 was removed from extrasynaptic sites and subsequently from synapses on motor neurons following INS.
- Treatment with a CP-AMPAR antagonist prevented INS-induced maladaptive plasticity and restored motor function during training.
Conclusions:
- Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in ventral horn motor neurons below a complete SCI.
- This plasticity involves changes in AMPAR composition, specifically the insertion of calcium-permeable AMPARs.
- Targeting CP-AMPARs offers a promising therapeutic strategy to mitigate maladaptive plasticity and improve motor recovery after SCI.
